Existing evidence indicates that only 40% of cases of ductal carcinoma in situ (DCIS) will eventually progress to invasive ductal carcinoma (IDC) if left untreated. However, due to a lack of availability of biomarkers and an insufficient understanding of the underlying molecular mechanisms of invasive progression, there is at present no clinically-useful way of predicting which DCIS will progress to become invasive. There is, therefore, a critical need to determine the underlying mechanisms and pathophysiology of DCIS progression to IDC. Our long- term goal is to help develop evidence-based clinically effective strategies to properly diagnose and treat DCIS. Towards this goal, we have developed a novel in vivo model of DCIS referred to as MIND (mouse-intraductal). This is the first model that mimics the entire process of breast cancer progression, including ductal growth as in situ lesions and their invasion as they escape the natural barriers of myoepithelial cells and the basement membrane. We have also utilized DCIS/IDC tandem lesions. Using both models, we have performed molecular profiling of DCIS at distinct stages of non-invasive to invasive transition. These studies showed significant up-regulation of several cancer related pathways and genes including a Wnt target gene and -catenin co-activator, BCL9 (B cell lymphoma-9). We focused on BCL9 because BCL9 has been shown to play a role in progression of other cancer types, while there is limited data in breast cancer. Our central hypothesis is that BCL9 promotes the formation of a pro-invasive tumor microenvironment by, 1) enhancement of canonical Wnt signaling in DCIS epithelium; and 2) Recruitment of stromal macrophages to DCIS. We propose the following two aims: Specific Aims: SA1. To evaluate the molecular mechanism(s) by which BCL9 expression in tumor epithelial cells promotes their invasive phenotype. SA2. To evaluate the role of BCL9 in formation of a DCIS pro-invasive stromal microenvironment by the recruitment of macrophages. The contribution of this research will be identifying and validating a biomarker, BCL9 that alone or in combination with other existing biomarkers can predict a future risk of IDC in DCIS patients and by doing so help guide decisions regarding treatment and follow-up. A biomarker that can identify DCIS patients who are not at risk for subsequent invasion could spare many women the morbidity (and cost) associated with unnecessary adjuvant medical and surgical therapy. Furthermore, if successful, our work will identify the BCL9/-catenin complex as important biological switch in the progression from DCIS to IDC that can be potentially targeted by therapeutics.